Irritable bowel syndrome affects 5-10% of North Americans, with an estimated one-third having a diarrhea-predominant form. Alosetron hydrochloride (Lotronex) is a serotonin receptor type 3 antagonist approved in early 2000 for use in women with diarrhea-predominant irritable bowel syndrome (IBS-D). Initial use was widespread, but infrequent serious adverse events of ischemic colitis and severe constipation-related complications prompted alosetron's voluntary withdrawal from the US market in November 2000. Unprecedented public request prompted its reintroduction in 2002 under a Risk Management Plan, including a more restricted indication and a Prescribing Program for Lotronex. Despite these measures, the use of alosetron has been very limited since its reintroduction. Possible deterrents to its use include concerns over safety and the possible medical-legal implications raised by the Risk Management Plan. It is also possible that changes in the natural history and/or diagnosis of IBS-D have reduced the target population. Given the unique regulatory history of alosetron, these issues continue to engender controversy. This article profiles these concerns and reviews the pharmacology, clinical efficacy and safety, and post-marketing experience with alosetron. Myths and misconceptions related to alosetron use, or lack thereof, are addressed to provide the reader with the evidence needed to make informed treatment decisions for their female patients with severe IBS-D.